There are four valves in the heart that direct the flow of blood through the two sides of the heart and out to the various organs of the body. The valves located on the left (systemic) side of the heart are: 1) the mitral valve, located between the left atrium and the left ventricle, and 2) the aortic valve, located between the left ventricle and the aorta. These two valves direct oxygenated blood coming from the lungs, through the left side of the heart and into the aorta for distribution to the body. On the right (pulmonary) side of the heart are: 1) the tricuspid valve, located between the right atrium and the right ventricle, and 2) the pulmonary valve, located between the right ventricle and the pulmonary artery. These two valves direct deoxygenated blood coming from the body, through the right side of the heart, into the pulmonary artery for distribution to the lungs, where it again becomes re-oxygenated to begin the circuit anew.
All four of these heart valves are passive structures in that they do not themselves expend any energy and do not perform any active contractile function. They consist of movable "leaflets" that are designed to open and close in response to differential pressures on either side of the valve. The mitral and tricuspid valves are referred to as "atrioventricular valves" because they are located between an atrium and a ventricle of the heart. The mitral valve has two leaflets whereas the tricuspid valve has three leaflets. The aortic and pulmonary valves each have three leaflets, which are more aptly termed "cusps".
Over 150,000 surgical procedures are performed each year to replace diseased cardiac valves worldwide. Two out of three procedures currently employ mechanical valve prostheses. Mechanical valves include caged-ball valves (such as Starr-Edwards valves), bi-leaflet valves (such as St. Jude valves), and titling disk valves (such as Medtronic-Hall or Omniscience valves). Caged ball valves typically comprise a ball made of a silicone rubber located inside a titanium cage, while bi-leaflet and tilting disk valves are made of various combinations of pyrolytic carbon and titanium. All of these valves have a cloth (usually Dacron.TM.) sewing ring so that the valve prosthesis can be sutured to the patient's native tissue to secure the implanted artificial valve.
The main advantage of mechanical valves is their long-term durability. However, currently available mechanical valves suffer from the disadvantage that they are thrombogenic and thus the patient requires lifetime anticoagulant therapy. If blood clots form on the valve, they may preclude the valve from opening or closing correctly or, more importantly, the blood clots may disengage from the valve and embolize to the brain, causing a stroke. Anticoagulant drugs can be administered to reduce the risk of blood clot formation, however such drugs are expensive and potentially dangerous in that they may cause abnormal bleeding which, in itself, can cause a stroke if the bleeding occurs within the brain.
One alternative to mechanical valves are valves constructed from natural tissues. Artificial valves constructed from natural tissues have superior hemodynamic characteristics, and accordingly the clinical use of tissue-based valves is growing faster than the overall valvular prosthesis market. Currently available tissue valves are constructed either by sewing the leaflets of pig aortic valves to a stent (to hold the leaflets in proper position), or by constructing valve leaflets from the pericardial sac (which surrounds the heart) of cows or pigs and sewing them to a stent. The stents may be rigid or slightly flexible and are covered with cloth (usually a synthetic material sold under the trademark Dacron.TM.) and attached to a sewing ring for fixation to the patient's native tissue. Three tissue valves have been approved by the US FDA for implantation: the Carpentier-Edwards Porcine Valve, the Hancock Porcine Valve, and the Carpentier-Edwards Pericardial Valve.
The main advantage of tissue valves is that they do not cause blood clots to form as readily as do the mechanical valves, and therefore, they do not absolutely require systemic anticoagulation. The major disadvantage of tissue valves is that they lack the long-term durability of mechanical valves. Currently available tissue valves have a significant failure rate, usually appearing at approximately 8-10 years following implantation. In particular, currently available tissue valve prothesis calcify after implantation, and calcification of the valves produces stiff leaflets which often crack.
Thus there is a need for a tissue valve construct that has long term durability and is biocompatible with host tissues. The present invention is directed to artificial tissue valves formed from warm-blooded vertebrate submucosal tissue. Submucosal tissue, prepared in accordance with the present invention, has been previously described as a biocompatible, non-thrombogenic graft material that enhances the repair of damaged or diseased host tissues. Numerous studies have shown that warm-blooded vertebrate submucosa is capable of inducing host tissue proliferation, and remodeling and regeneration of tissue structures following implantation in a number of in vivo microenvironments including lower urinary tract, body wall, tendon, ligament, bone, cardiovascular tissues and the central nervous system. Upon implantation, cellular infiltration and a rapid neovascularization are observed and the submucosa material is remodeled into host replacement tissue with site-specific structural and functional properties.
Submucosal tissue can be obtained from various tissue sources, harvested from animals raised for meat production, including, for example, pigs, cattle and sheep or other warm-blooded vertebrates. More particularly, the submucosa is isolated from warm-blooded tissues including the alimentary, respiratory, intestinal, urinary or genital tracts of warm-blooded vertebrates. In general submucosa is prepared from these tissue sources by delaminating the submucosa from both the smooth muscle layers and the mucosal layers. The preparation of intestinal submucosa is described and claimed in U.S. Pat. No. 4,902,508, the disclosure of which is expressly incorporated herein by reference. Urinary bladder submucosa and its preparation is described in U.S. Pat. No. 5,554,389, the disclosure of which is expressly incorporated herein by reference. Stomach submucosa has also been obtained and characterized using similar tissue processing techniques. Such is described in U.S. patent application Ser. No. 60/032,683 entitled STOMACH SUBMUCOSA DERIVED TISSUE GRAFT, filed on Dec. 10, 1996. Briefly, stomach submucosa is prepared from a segment of stomach in a procedure similar to the preparation of intestinal submucosa. A segment of stomach tissue is first subjected to abrasion using a longitudinal wiping motion to remove the outer layers (particularly the smooth muscle layers) and the luminal portions of the tunica mucosa layers. The resulting stomach submucosa tissue has a thickness of about 100 to about 200 micrometers, and consists primarily (greater than 98%) of acellular, eosinophilic staining (H&E stain) extracellular matrix material.
Preferred submucosal tissues for use in accordance with this invention include intestinal submucosa, stomach submucosa, urinary bladder submucosa, and uterine submucosa. Intestinal submucosal tissue is one preferred starting material, and more particularly intestinal submucosa delaminated from both the tunica muscularis and at least the tunica mucosa of warm-blooded vertebrate intestine.
As a tissue graft, submucosal tissue undergoes remodeling and induces the growth of endogenous tissues upon implantation into a host. It has been used successfully in vascular grafts, urinary bladder and hernia repair, replacement and repair of tendons and ligaments, and dermal grafts. The preparation and use of submucosa as a tissue graft composition is described in U.S. Pat. Nos. 4,902,508; 5,281,422; 5,275,826; 5,554,389; and other related U.S. patents. When used in such applications, the graft constructs appear not only to serve as a matrix for the regrowth of the tissues replaced by the graft constructs, but also promote or induce such regrowth of endogenous tissue. Common events to this remodeling process include: widespread and very rapid neovascularization, proliferation of granulation mesenchymal cells, biodegradation/resorption of implanted intestinal submucosal tissue material, and lack of immune rejection.
Submucosal tissue is also capable of promoting endogenous regrowth and healing of damaged or diseased cardiac tissues, including the endocardium, pericardium, and myocardium. In particular, damaged or diseased myocardial tissues can be replaced in vivo with a composition comprising submucosal tissue of a warm blooded vertebrate to enhance the formation of endogenous tissues having spontaneous contractile properties.
The present invention is directed to the use of submucosal tissue to prepare tissue valve constructs, and the use of those valve constructs to replace or repair damaged or diseased valves of the heart and the circulatory system of a warm-blooded vertebrate.